Fluid management flow implants of improved occlusion resistance

ABSTRACT

This invention relates to achieving or improving uniform distribution of fluid flow in medical devices such as when combined with antibiotics impregnated in a catheter and/or with a drug-eluting catheter to further inhibit the catheter from becoming occluded by debris in the CSF or by bacterial biofilm formation or tissue proliferation in the catheter.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to fluid management flow devices such as acatheter device and methods useful with such devices, and in particularhydrocephalus shunts containing an antibiotic and/or drug to minimizethe risk of blockage or obstruction inside of the catheter whileimproving protection against colonization of gram-positive bacteriaand/or tissue proliferation when the devices are combined with uniformfluid flow enhancing tips.

2. Related Art

Hydrocephalus is a neurological condition that is caused by the abnormalaccumulation of cerebrospinal fluid (CSF) within the ventricles, orcavities, of the brain. CSF is a clear, colorless fluid that isprimarily produced by the choroid plexus and surrounds the brain andspinal cord. CSF constantly circulates through the ventricular system ofthe brain and is ultimately absorbed into the bloodstream. CSF aids inthe protection of the brain and spinal cord. Because CSF keeps the brainand spinal cord buoyant, it acts as a protective cushion or “shockabsorber” to prevent injuries to the central nervous system.

Hydrocephalus, which affects children and adults, arises when the normaldrainage of CSF in the brain is blocked in some way. Such blockage canbe caused by a number of factors, including, for example, geneticpredisposition, intraventricular or intracranial hemorrhage, infectionssuch as meningitis, head trauma, or the like. Blockage of the flow ofCSF consequently creates an imbalance between the amount of CSF producedby the choroid plexus and the rate at which CSF is absorbed into thebloodstream, thereby increasing pressure on the brain, which causes theventricles to enlarge.

Some of these problems can be treated by backflushing, which is aprocess that uses the CSF present in the shunt system to remove theobstructing matter. This process can be ineffective, however, due to thesmall size of the pores of the ventricular catheter and due to the smallamount of flushing liquid available in the shunt system. Other shuntsystems have been designed to include a mechanism for flushing the shuntsystem. For example, some shunt systems include a pumping device withinthe system which causes fluid in the system to flow with considerablepressure and velocity, thereby flushing the system. As with the processof backflushing, using a built-in mechanism to flush the shunt systemcan also fail to remove the obstruction due to factors such as the sizeof the pores and the degree and extent to which the pores have beenclogged.

Occluded ventricular catheters can also be repaired by cauterizing thecatheter to remove blocking tissue, thereby reopening existing poresthat have become occluded. Alternatively, new pores can be created inthe catheter. These repairs, however, may be incapable of removingobstructions from the ventricular catheter depending on the location ofthe clogged pores. Additionally, the extent of tissue growth into andaround the catheter can also preclude the creation of additional pores,for example, in situations where the tissue growth covers a substantialportion of the ventricular catheter. Another disadvantage of creatingnew apertures to repair an occluded ventricular catheter is that thismethod fails to prevent or reduce the risk of repeated obstructions.

Because attempts at flushing or repairing a blocked ventricular catheterare often futile and ineffective, occlusion is more often treated byreplacing the catheter. Although this can be accomplished by simplyremoving the obstructed catheter from the ventricle, the growth of thechoroid plexus and other tissues around the catheter and into the porescan hinder removal and replacement of the catheter. Care must beexercised to avoid damage to the choroid plexus, which can cause severeinjury to the patient, such as, for example, hemorrhaging. Not only dothese procedures pose a significant risk of injury to the patient, theycan also be very costly, especially when shunt obstruction is arecurring problem

U.S. Pat. No. 4,917,686, the disclosure of which is hereby incorporatedby reference, describes implanted medical devices (such catheters,valves, molded parts, etc. and including hydrocephalus shunts andcentral venous catheters) that have been treated with antimicrobialagents to combat the problem of colonization of bacteria particularly onthe interior surfaces of the device.

US 2003/0216710, the disclosure of which is whereby incorporated byreference, describes a catheter having one or more inlet holes along thelength of the catheter whereby the cross-sectional areas of successiveinlet holes decreases, the decrease first occurring at the inlet holeimmediately following the most proximal inlet hole. Such a designpurports to alter the typical inflow of fluid into the catheter suchthat a disproportionately high volume of fluid no longer enters the mostproximal inlet hole. The decrease in inflow at the most proximal inletresults in less deposition of debris within the catheter at thisposition.

Lin et al., in “Computational and Experimental Study of Proximal Flow inVentricular Catheters”, (J. Neurosurgery 99:426-431, 2003), thedisclosure of which is hereby incorporated by reference, describes anddemonstrates that drainage hole geometry is indeed a factor in achievinguniform flow patterns within ventricular catheters. FIG. 2 of Lindramatically demonstrates the flow distribution improvement whencatheter hole geometry is modified. The problem addressed by Lin relatesto obstructing agents such as blood clots, cell clusters and normaltissue as causing occlusion of the catheter at its proximal end. Thereis no mention of antimicrobial or drug based implantable medical devicessuch as catheters or shunts in an attempt to alleviate occlusion of thecatheter lumen caused by biofilm formation through bacterialcolonization or occlusion by tissue proliferation.

Accordingly, there exists a need for fluid management flow implants,such as shunts and catheter shunt systems that minimize or eliminate therisk of blockage or obstruction in the implant and reduces thepossibility of bacterial biofilm or tissue occlusion within the lumensand inner surfaces of the implants.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 a depicts the first step in staphylococcal biofilm formation thatof adhesion of staphylococcal cells to a surface.

FIG. 1 b depicts the second step in staphylococcal biofilm formation,that of multiplication of cells and production of a slime matrix.

FIGS. 2 a and 2 b depict a comparison showing the perceived benefits ofantibiotic or drug release for a catheter with uniform fluid flowdistribution through catheter holes compared with non-uniform fluid flowdistribution.

FIG. 3 depicts an embodiment of a fluid flow enhancing distribution tip.

SUMMARY OF THE INVENTION

One embodiment of this invention relates to a method of minimizingformation of bacterial biofilm or tissue proliferation in implantablefluid management systems comprising:

-   -   a) providing an implant comprising an antimicrobial or        drug-eluting catheter having a proximal and distal end;    -   b) providing a flow distribution enhancing tip at the distal end        of the catheter;    -   c) inserting the distal end of the catheter into an area to be        drained;    -   d) placing the proximal end of the catheter in a selected area        inside or outside of the human body; and    -   e) draining fluid from the area to be drained to the selected        area through the catheter.

Another embodiment of this invention relates to a fluid managementsystem comprising:

-   -   a) an antimicrobial or drug-eluting device comprising a proximal        and distal end; and    -   b) a flow distribution enhancing tip at the distal end of the        device.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

The present invention is directed toward fluid management flow implantssuch as catheter drainage devices, preferably hydrocephalus shunts,which contain antibiotics to prevent or reduce the risk of infection andslime formation in the interior surfaces of the catheter and/or a drugto prevent or minimize tissue growth, combined with a flow distributionenhancing tip. This combination device will potentially minimize therisk of blockage or obstruction of the lumens and inner surfaces of theimplants due to either biofilm formation or tissue in-growth and allow agreater chance of uninterrupted fluid flow which will in turn lessen thelikelihood for costly revision surgery or procedures.

Lundberg et al.: Presence of vitronectin and activated complement factorC9 on ventriculoperitoneal shunts and temporary ventricular drainagecatheters. J Neurosurg 1999, 90: 101-108 and Bayston & Penny: Excessiveproduction of mucoid substance by Staphylococcus SIIA: a possible factorin colonization of Holter shunts. Dev Med Child Neurol 1972: 14 Suppl27: 25-28 recognized that adhesion of bacteria to an implant surface isa critical initial step in the development of biomaterial-centeredinfections. Also, F. Gotz and G. Peters: Colonization of Medical Devicesby Coagulase-Negative Staphylococci. In: Infections Associated withIndwelling Medical Devices. F. A. Waldvogel and A. L. Bisno eds., ASMPress, Washington, D.C., 2000, p. 69. report that ventricular CSFcultures in patients with symptoms of shunt infection are frequentlynegative and the shunt cultures are positive, indicating shuntcolonization is a key element of shunt-related infections. The primaryadhesion event is mediated by binding proteins on the bacterial surface.Bactiseal catheters are specifically designed to provide extendedprotection from colonization of the silicone surface bycoagulase-negative bacteria such as S epidermidis.

FIGS. 1 a and 1 b describe the above described two step model of biofilmformation. FIG. 1 a shows the first step in biofilm formation which isthe adherence of the bacterial cells 2 to a surface 1. In FIG. 1 b, thesecond step is the imbedding of the cells 2 into a thick slime matrix(biofilm) 3.

The flow distribution enhancing tip may be any type of tip that enablesuniform flow patterns within the medical device. For example, in thecase of a catheter, tip designs that help promote uniform flowdistribution within the catheter are contemplated. The terms “uniformflow pattern” or “uniform flow distribution” are intended to describe atip which improves fluid flow over tips not so designed. By providingmore uniform fluid flow in the implants, particularly with in the lumensof catheters and hydrocephalus shunts, more uniform release ofantimicrobial agents and drugs are achieved which in turn should provideimproved resistance to flow occlusion caused by bacterial biofilms andtissue proliferation.

FIGS. 2 a and 2 b depict the perceived benefit of a flow enhancing tipused in combination with antimicrobial agents and/or drugs compared withantimicrobial agents and/or drugs not combined with a flow enhancingtip.

Referring to FIG. 2 a, tip 10 is shown with apertures 12 of varyingcross-sectional area. As one proceeds from the distal end to theproximal end of tip 10, apertures 12 decrease in cross-sectional area.This aperture geometry helps to promote uniform flow which in turn isexpected to promote uniform release of antimicrobial agents or drugs 14.

In contrast, and now referring to FIG. 2 b, conventional tip 10 is shownwith apertures 12 of constant cross-sectional area. Fluid flow enteringthrough apertures 12 will not produce a uniform flow with tip 10 andtherefore release of antimicrobial agents or drugs 14 is not expected tobe uniform.

Examples of suitable flow distribution enhancing tips may be found. Forexample, in US 2003/0216710 and Lin, infra, the disclosures of which arehereby incorporated by reference.

More specifically, Lin, infra, discloses theoretical and experimentaldata showing that more than 80% of total fluid mass flows into the twomost proximal holes of a hydrocephalus shunt. Catheters with variablesized holes, with its largest one situated at the catheter tip, wouldredistribute the flow more evenly along the entire length of thecatheter. Therefore, favorable changes in the geometry of the proximalcatheter can significantly alter the fluid dynamics of the catheter,which in itself may ultimately lead to a decrease in the rate ofproximal catheter obstruction and when coupled with antimicrobial agentsand/or drugs and provide more even release of the antimicrobial agentsand/or drugs to more effectively combat bacterial biofilms and/ortissues proliferation. Thus, an example of a suitable tip geometrycomprises a tip with a hole pattern of varying hole size where thelargest hole is at the distal end of the catheter tip and the smallesthole in the pattern is closest to the shunt valve. Most preferred is awhole geometry as depicted in FIG. 3 wherein the size of the holesprogressively increase in cross-sectional area from the most proximalinlet hole to the most distal inlet hole.

In one embodiment, the flow enhancing tip may further comprise a porousdevice that is incorporated into or onto the tip to reduce thelikelihood of blockage by tissue ingrowth. The device may also be usedto dialyze the fluid surrounding the catheter. It is envisioned that thepores would be less than 5 μm in their largest dimension, and preferablyless than 1 μm, to prevent tissue structures and a supporting bloodsupply from growing into the luminal space. The device may be attachedto the outside surface of the catheter, or it may be inserted into thelumen. Alternatively, the device may be integrated into the cathetermaterial in such a way as to produce a composite structure.

The porous device may have pore sizes of subnano-, nano- ormicroporosity to selectively exclude blood vessels, cells, biologicaldebris or molecules of a specific size from the lumen of the catheter.The purpose of the porous aspect of the device is also to preventcatheter obstruction due to tissue ingrowth. The device may also be usedto dialyze the fluid surrounding the catheter.

The porous device may be attached to the inside and/or outside surfacesof all or part of the catheter. The device may also be incorporated intothe catheter material on may comprise a sleeve which fits over acatheter tip. The pore size is ideally less than 1 μm to preventcellular migration into the lumen of the catheter and the development oftissue structures and a supporting blood supply. The porous devicedescribed in this invention may also be used to prevent blockage at theproximal or distal end of a hydrocephalus catheter, or at the outlet ofa drug delivery catheter, or at the end of another fluid managementcatheter. The pore size of the device may also be chosen such that onlymolecules of a specific size range are allowed to pass into thecatheter.

The porous device may be fabricated from metal, ceramic, a selected bulkpolymer or a polymer film. The pores may be created by manufacturingprocesses including but not limited to laser drilling, chemical etching,controlled sintering, or incorporating leachable additives orpore-forming agents.

The fluid discharge from the devices of this invention may be toselected areas inside or outside of the human body. Typical selecteddischarge areas inside the human body include the peritoneum, the rightatrium of the heart, the pleural cavity, and the bladder. The commonselected discharge areas outside the human body include fluid collectionchambers such as drainage bags.

As used herein, antimicrobial agents are intended to encompass thoseagents that prevent or minimize bacterial colonization and are intendedto include but not be limited to antibiotics, antiseptics anddisinfectants.

Examples of suitable antibiotics include tetracyclines (e.g.,minocycline), rifamycins (e.g., rifampin), macrolides (e.g.,erythromycin), penicillins (e.g., nafcillin), cephalosporins (e.g.,cefazolin), other beta-lactam antibiotics (e.g., imipenem, aztreonam),aminoglycosides (e.g., gentamicin), chloramphenicol, sulfonamides (e.g.,sulfamethoxazole), glycopeptides (e.g., vancomycin), quinolones (e.g.,ciprofloxacin), fusidic acid, trimethoprim, metronidazole, clindamycin,mupirocin, polyenes (e.g., amphotericin B), azoles (e.g., fluconazole)and beta-lactam inhibitors (e.g., sulbactam).

Examples of preferred antibiotics include minocycline, rifampin,erythromycin, nafcillin, cefazolin, imipenem, aztreonam, gentamicin,sulfamethoxazole, vancomycin, ciprofloxacin, trimethoprim,metronidazole, clindamycin, teicoplanin, mupirocin, azithromycin,clarithromycin, ofloxacin, lomefloxacin, norfloxacin, nalidixic acid,sparfloxacin, pefloxacin, amifloxacin, enoxacin, fleroxacin,temafloxacin, tosufloxacin, clinafloxacin, sulbactam, clavulanic acid,amphotericin B, fluconazole, itraconazole, ketoconazole, and nystatin.

Examples of antiseptics and disinfectants are hexachlorophene, cationicbisiguanides (e.g., chlorhexidine, cyclohexidine) iodine and iodophores(e.g., povidone-iodine), para-chloro-meta-xylenol, triclosan, furanmedical preparations (e.g., nitrofurantoin, nitrofurazone), methenamine,aldehydes (glutaraldehyde, formaldehyde) and alcohols.

The most preferred antimicrobials are rifampin and clindamycinhydrochloride. Together they provide superior penetration and persistentantimicrobial activity in devices treated. The antimicrobial activitycovers most strains of gram-positive bacteria causing the majority ofinfections in medical devices such as hydrocephalus shunts.

As used herein, the term drugs are intended to encompass drugs thatprevent or minimize tissue growth whether the drugs are cytostatic drugsor cytotoxic drugs.

Non-limitative examples of drugs include therapeutic and pharmaceuticagents including: anti-proliferative/antimitotic agents includingnatural products such as vinca alkaloids (e.g., vinblastine,vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (e.g.,etoposide, teniposide), antibiotics (dactinomycin (actinomycin D)daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone,bleomycins, plicamycin (mithramycin) and mitomycin, enzymes(L-asparaginase which systemically metabolizes L-asparagine and deprivescells which do not have the capacity to synthesize their ownasparagine); antiplatelet agents such as G(GP) ll_(b)/lll_(a) inhibitorsand vitronectin receptor antagonists; anti-proliferative/antimitoticalkylating agents such as nitrogen mustards (mechlorethamine,cyclophosphamide and analogs, melphalan, chlorambucil), ethyleniminesand methylmelamines (hexamethylmelamine and thiotepa), alkylsulfonates-busulfan, nirtosoureas (carmustine (BCNU) and analogs,streptozocin), trazenes—dacarbazinine (DTIC);anti-proliferative/antimitotic antimetabolites such as folic acidanalogs (methotrexate), pyrimidine analogs (fluorouracil, floxuridine,and cytarabine), purine analogs and related inhibitors (mercaptopurine,thioguanine, pentostatin and 2-chlorodeoxyadenosine {cladribine});platinum coordination complexes (cisplatin, carboplatin), procarbazine,hydroxyurea, mitotane, aminoglutethimide; hormones (e.g., estrogen);anti-coagulants (heparin, synthetic heparin salts and other inhibitorsof thrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory; antisecretory (breveldin);anti-inflammatory: such as adrenocortical steroids (cortisol, cortisone,fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone,triamcinolone, betamethasone, and dexamethasone), non-steroidal agents(salicylic acid derivatives e.g., aspirin; para-aminophenol derivativese.g., acetaminophen; indole and indene acetic acids (indomethacin,sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac,and ketorolac), arylpropionic acids (ibuprofen and derivatives),anthranilic acids (mefenamic acid, and meclofenamic acid), mycophenolicacids, enolic acids (piroxicam, tenoxicam, phenylbutazone, andoxyphenthatrazone), nabumetone, gold compounds (auranofin,aurothioglucose, gold sodium thiomalate); immunosuppressives:(cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine,mycophenolate mofetil); angiogenic agents: vascular endothelial growthfactor (VEGF), fibroblast growth factor (FGF); angiotensin receptorblockers; nitric oxide donors; antisense oligionucleotides andcombinations thereof; cell cycle inhibitors, mTOR inhibitors, and growthfactor receptor signal transduction kinase inhibitors; retenoids;cyclin/CDK inhibitors; HMG co-enzyme reductase inhibitors (statins); andprotease inhibitors.

A preferred cytostatic drug is sirolimus (rapamycin) particularly incombination with mycophenolic acid.

A preferred cytotoxic drug is paclitaxel.

Non-limiting examples of fluid flow control devices and systems includecatheters, shunts, hydrocephalus shunts, central nervous catheters,dialysis grafts, and ear drainage tubes.

While many types of methods may be used to combine an antimicrobialagent or drug with the fluid flow control system of the presentinvention such as by coating or impregnation, impregnation is preferredwhen dealing with medical devices made of polymeric materials such assilicone elastomers.

U.S. Pat. No. 4,917,686 describes a preferred method of incorporatingantimicrobial agents within medical devices and such disclosure ishereby incorporated by reference.

The antimicrobial agent and/or drug may also be coated on the insideand/or outside surfaces of all or part of the implant. The drug may beincorporated into the catheter material such that it diffuses from theinside and/or outside surfaces of the tip of the catheter in the regionwhere the fluid drainage holes are located. Alternatively, a porous orother type of sleeve, made from a material that contains the drug(s) maybe placed over the outside and/or into the inside lumen of the proximaltip of the catheter in the region where the fluid drainage holes arelocated.

The impregnation process can be altered to leave an antimicrobial agentand/or drug on the surface. A top-coat that can be used to modulate theelution profile from either the surface or the bulk of the catheterand/or localize the effect of the drug is also being explored. Thetop-coat can range from a monolayer to a thick layer of syntheticpolymer or protein, carbohydrate, or glycoprotein. The coatings cancomprise combinations of the previous classes of molecules. In addition,grafted molecules consisting of combinations of synthetic and naturalpolymers can be used in the form of dendrimers, star, comb or blockcopolymers. The top-coat can contain drug or could be drug free. Bothhydrophilic and or hydrophobic synthetic polymers could be used. Forexample polyethylene oxide based polymer systems have been widely usedas coatings as have fluorinated polymers and copolymers. Layered systemscould provide special benefits. Heparin-based polymer systems as well asother sulfated proteoglycan systems (such as chondroitin sulfate) havealso been widely used as coatings. Topcoats consisting of laminatedlayers of these constituents are also contemplated. Such topcoats couldbe used to reduce the rate of drug elution or provide an immediate burstof particular drugs.

Spatially unhomogeneous topcoats are also described here. These systemscan consist of thicker topcoat layers in the vicinity of drainageorifices or have different materials printed in layers onto differentpoints along the surface of the catheter tip. In addition, differentdrugs or different concentrations of drugs can be laid down at differentpoints along the surface of the catheter tip. The goal would be toproduce local effects at the orifices in the catheter tip and may beadvantageous where very expensive drugs or polymer materials are beingused.

Antiomicrobial agents or drugs can be both physically entrapped as wellas covalently grafted in the topcoat layers. Covalently grafted drugswould either inhibit cell attachment by interfering with cell membranefunction or would be slowly released by cleavage of labile linkages.Cleavage could either be by chemical or proteolytic mechanisms.

Numerous processes for depositing drug or coatings may be used inconjunction with this invention. Most simply, antimicrobial agent(s)and/or drug(s) are impregnated into the bulk of the catheter either bycompounding-in the drug when the catheter is molded (if the drug isstable to this process) or by impregnating the catheter with drugpost-molding. Impregnation can be accomplished by using a solvent orco-solvent system to swell the polymer and diffuse-in the antimicrobialagents/drugs, followed by evaporation of the solvents to entrap theantimicrobial agent/drugs. Impregnation by supercritical fluids orsupercritical fluid-organic co-solvent fluids is also described toreduce the quantity of organic solvent needed. The advantage here isprimarily ecological (reduced toxic pollutants), but also uniquedrug-polymer microstructures and release-profiles are possible. Bylimiting the exposure time of the catheter to the antimicrobialagent/drug-solvent solution, an antimicrobial agent/drug loading profilethat varies through the thickness of the coating can be achieved. Thistype of process can provide higher surface concentrations of theantimicrobial agents/drugs. In addition to depositing the antimicrobialagents/drugs in the bulk of the catheter, antimicrobial agents/drugs canalso be included in a sprayed-on coating or dip-coated topcoat. Surfacevariable coatings can be achieved by masking the implants such ascatheters in a spraying process or by selectively spraying only certainareas. Selective material layers can be added by sequentially buildingup different layers. Finally, coatings can be applied or modified usingchemical vapor deposition or plasma coating processes. This can also bedesirable for preventing delamination of laminated coatings.

It should be understood that the foregoing disclosure and description ofthe present invention are illustrative and explanatory thereof andvarious changes in the size, shape and materials as well as in thedescription of the preferred embodiment may be made without departingfrom the spirit of the invention.

1. A method of minimizing formation of bacterial biofilm or tissueproliferation in implantable fluid management systems comprising: a.providing an implant comprising an antimicrobial or drug-elutingcatheter having a proximal and distal end; b. providing a flowdistribution enhancing tip at the distal end of the catheter; c.providing a filter inserted in or around the flow distribution enhancingtip; d. inserting the distal end of the catheter into an area to bedrained; e. placing the proximal end of the catheter in a selected areainside or outside of the human body; and f. draining fluid from the areato be drained to the selected area through the catheter.
 2. The methodof claim 1, wherein the flow distribution enhancing tip comprises adistal end which is sealed and a plurality of inlet apertures locatedbetween the distal and proximal ends of the tip.
 3. The method of claim2, wherein the flow distribution enhancing tip comprises an inletaperture geometry wherein the inlet apertures progressively increase incross-sectional area from the most proximal inlet aperture to the mostdistal inlet aperture.
 4. The method of claim 1 wherein theantimicrobial catheter comprises an antimicrobial agent selected fromthe group consisting of tetracyclines, rifamycins, macrolides,penicillins, cephalosporins, other beta-lactam antibiotics,aminoglycosides, chloramphenicol, sulfonamides, glycopeptides,quinolones, fusidic acid, trimethoprim, metronidazole, clindamycins,mupirocin, polyenes, azoles, beta-lactam inhibitors and mixturesthereof.
 5. The method of claim 4 wherein the antimicrobial agent isselected from the group consisting of isminocycline, rifampin,erythromycin, nafcillin, cefazolin, imipenem, aztreonam, gentamicin,sulfamethoxazole, vancomycin, ciprofloxacin, trimethoprim,metronidazole, clindamycin, teicoplanin, mupirocin, azithromycin,clarithromycin, ofloxacin, lomefloxacin, norfloxacin, nalidixic acid,sparfloxacin, pefloxacin, amifloxacin, enoxacin, fleroxacin,temafloxacin, tosufloxacin, clinafloxacin, sulbactam, clavulanic acid,amphotericin B, fluconazole, itraconazole, ketoconazole, nystatin andmixtures thereof.
 6. The method of claim 4 wherein the antimicrobialagent is selected from the group consisting of rifampin, clindamycinhydrochloride and mixtures thereof.
 7. The method of claim 4, whereinthe wherein the flow distribution enhancing tip comprises a distal endwhich is sealed and a plurality of inlet apertures located between thedistal and proximal ends of the tip.
 8. The method of claim 4, whereinthe wherein the flow distribution enhancing tip comprises an inletaperture geometry wherein the inlet apertures progressively increase incross-sectional area from the most proximal inlet aperture to the mostdistal inlet aperture.
 9. The method of claim 1 wherein the drug-elutingcatheter comprises a drug selected from the group consisting of vincaalkaloids, paclitaxel, epidipodophyllotoxins, anthracyclines,mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin,enzymes; antiplatelet agents; anti-proliferative/antimitotic alkylatingagents; anti-proliferative/antimitotic antimetabolites; platinumcoordination complexes; hormones; anti-coagulants; fibrinolytic agents;anti-inflammatory steriods, non-steroidal agents; para-aminophenolderivatives; indole and indene acetic acids, heteroaryl acetic acids,mycophenolic acids, enolic acids, nabumetone, gold compounds;immunosuppressives; sirolimus (rapamycin), azathioprine, mycophenolatemofetil); angiogenic agents: vascular endothelial growth factor (VEGF),fibroblast growth factor (FGF); angiotensin receptor blockers; nitricoxide donors; antisense oligionucleotides and combinations thereof; cellcycle inhibitors, mTOR inhibitors, and growth factor receptor signaltransduction kinase inhibitors; retenoids; cyclin/CDK inhibitors; HMGco-enzyme reductase inhibitors (statins); protease inhibitors andmixtures thereof.
 10. The method of claim 1 wherein the drug comprisespaclitaxel.
 11. The method of claim 1 wherein the drug comprisessirolimus and mycophenolic acid.
 12. The method of claim 1 wherein thedrug comprises sirolimus.
 13. A fluid management system comprising: a)an antimicrobial or drug-eluting device comprising a proximal and distalend; and b) a flow distribution enhancing tip at the distal end of thedevice, wherein the flow distribution enhancing tip further comprises afilter inserted in or around the tip.
 14. The system of claim 13,wherein the device is selected from the group consisting of catheters,shunts, hydrocephalus shunts, central nervous catheters, dialysisgrafts, and drainage tubes.
 15. The system of claim 14, wherein thedevice is a catheter.
 16. The system of claim 14, wherein the device isa hydrocephalus shunt.
 17. The system of claim 13, wherein the devicecomprises antimicrobial agents selected from the group consisting oftetracyclines, rifamycins, macrolides, penicillins, cephalosporins,other beta-lactam antibiotics, aminoglycosides, chloramphenicol,sulfonamides, glycopeptides, quinolones, fusidic acid, trimethoprim,metronidazole, clindamycins, mupirocin, polyenes, azoles, beta-lactaminhibitors and mixtures thereof.
 18. The system of claim 17, wherein theantimicrobial agent is selected from the group consisting ofisminocycline, rifampin, erythromycin, nafcillin, cefazolin, imipenem,aztreonam, gentamicin, sulfamethoxazole, vancomycin, ciprofloxacin,trimethoprim, metronidazole, clindamycin, teicoplanin, mupirocin,azithromycin, clarithromycin, ofloxacin, lomefloxacin, norfloxacin,nalidixic acid, sparfloxacin, pefloxacin, amifloxacin, enoxacin,fleroxacin, temafloxacin, tosufloxacin, clinafloxacin, sulbactam,clavulanic acid, amphotericin B, fluconazole, itraconazole,ketoconazole, nystatin and mixtures thereof.
 19. The system of claim 17,wherein the antimicrobial agent is selected from the group consisting ofrifampin, clindamycin hydrochloride and mixtures thereof.
 20. The systemof claim 13, wherein the flow distribution enhancing tip comprises adistal end which is sealed and a plurality of inlet apertures locatedbetween the distal and proximal ends of the tip.
 21. The system of claim20, wherein the flow distribution enhancing tip comprises an inletaperture geometry wherein the inlet apertures progressively decrease incross-sectional area from the most proximal inlet aperture to the mostdistal inlet aperture.
 22. The system of claim 13, wherein the drug inthe drug-eluting device comprises a drug selected from the groupconsisting of vinca alkaloids, paclitaxel, epidipodophyllotoxins,anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) andmitomycin, enzymes; antiplatelet agents; anti-proliferative/antimitoticalkylating agents; anti-proliferative/antimitotic antimetabolites;platinum coordination complexes; hormones; anti-coagulants; fibrinolyticagents; anti-inflammatory steriods, non-steroidal agents;para-aminophenol derivatives; indole and indene acetic acids, heteroarylacetic acids, mycophenolic acids, enolic acids, nabumetone, goldcompounds; immunosuppressives; sirolimus (rapamycin), azathioprine,mycophenolate mofetil); angiogenic agents: vascular endothelial growthfactor (VEGF), fibroblast growth factor (FGF); angiotensin receptorblockers; nitric oxide donors; antisense oligionucleotides andcombinations thereof; cell cycle inhibitors, mTOR inhibitors, and growthfactor receptor signal transduction kinase inhibitors; retenoids;cyclin/CDK inhibitors; HMG co-enzyme reductase inhibitors (statins);protease inhibitors and mixtures thereof.
 23. The system of claim 22,wherein the drug comprises paclitaxel.
 24. The system of claim 22,wherein the drug comprises a combination of sirolimus and mycophenolicacid.
 25. The system of claim 22, wherein the drug comprises sirolimus.